ABCMdb

ABCC7 p.His949Leu

ClinVar:	c.2845C>T , p.His949Tyr D , Pathogenic c.2846A>T , p.His949Leu ? , not provided c.2846A>G , p.His949Arg ? , not provided
CF databases:	c.2846A>G , p.His949Arg (CFTR1) D , The above mutation was found by DGGE and direct sequencing in Caucasian patients. c.2845C>T , p.His949Tyr (CFTR1) ? , The nucleotide change C->T at position 2977 (codon 949 in exon 15, H949Y), has been found in a 60 years old woman with no manifestation of gastrointestinal disease but having a bronchial dilatation. c.2846A>C , p.His949Pro (CFTR1) ? , c.2846A>T , p.His949Leu (CFTR1) ? , The nucleotide change was found by DGGE followed by sequencing of both the strands. This mutation was identified in 4 male patients from Puglia, region of Southern Italy. This mutation was identified in cis with another mutation: H939R. This is a novel complex CFTR allele: H939R + H949L.
Predicted by SNAP2:	A: D (85%), C: D (85%), D: D (95%), E: D (95%), F: D (91%), G: D (91%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (95%), P: D (95%), Q: D (91%), R: D (95%), S: D (91%), T: D (91%), V: D (91%), W: D (95%), Y: D (53%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

[switch to compact view]
Comments [show]

None has been submitted yet.

Publications
[hide] Extensive sequencing of the CFTR gene: lessons lea... Hum Genet. 2005 Dec;118(3-4):331-8. Epub 2005 Sep 28. McGinniss MJ, Chen C, Redman JB, Buller A, Quan F, Peng M, Giusti R, Hantash FM, Huang D, Sun W, Strom CM
Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples.
Hum Genet. 2005 Dec;118(3-4):331-8. Epub 2005 Sep 28., [PMID:16189704]

Abstract [show]
Cystic fibrosis (CF) is one of the most common monogenic diseases affecting Caucasians and has an incidence of approximately 1:3,300 births. Currently recommended screening panels for mutations in the responsible gene (CF transmembrane regulator gene, CFTR) do not detect all disease-associated mutations. Our laboratory offers extensive sequencing of the CFTR (ABCC7) gene (including the promoter, all exons and splice junction sites, and regions of selected introns) as a clinical test to detect mutations which are not found with conventional screening. The objective of this report is to summarize the findings of extensive CFTR sequencing from our first 157 consecutive patient samples. In most patients with classic CF symptoms (18/24, 75%), extensive CFTR sequencing confirmed the diagnosis by finding two disease-associated mutations. In contrast, only 5 of 75 (7%) patients with atypical CF had been identified with two CFTR mutations. A diagnosis of CF was confirmed in 10 of 17 (58%) newborns with either positive sweat chloride readings or positive immunoreactive trypsinogen (IRT) screen results. We ascertained ten novel sequence variants that are potentially disease-associated: two deletions (c.1641AG>T, c.2949_2853delTACTC), seven missense mutations (p.S158T, p.G451V, p.K481E, p.C491S, p.H949L, p.T1036N, p.F1099L), and one complex allele ([p.356_A357del; p.358I]). We ascertained three other apparently novel complex alleles. Finally, several patients were found to carry partial CFTR gene deletions. In summary, extensive CFTR gene sequencing can detect rare mutations which are not found with other screening and diagnostic tests, and can thus establish a definitive diagnosis in symptomatic patients with previously negative results. This enables carrier detection and prenatal diagnosis in additional family members.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
7 We ascertained ten novel sequence variants that are potentially disease-associated: two deletions (c.1641AG>T, c.2949_2853delTACTC), seven missense mutations (p.S158T, p.G451V, p.K481E, p.C491S, p.H949L, p.T1036N, p.F1099L), and one complex allele ([p.356_A357del; p.358I]). Login to comment
86 Three novel missense mutations (p.S158T, p.K481E and p.H949L) are consistent with being disease-associated alleles, but the evidence for this was not as strong as for the three previously mentioned. Login to comment
89 One patient (p.H949L/wt) was positive for the 5T variant in intron 8 polyT locus, but the parental samples were not available to ascertain if the 5T allele was on the same or opposite chromosome as the p.H949L mutation. Login to comment

[hide] Genotype-phenotype correlation in cystic fibrosis ... Genet Mol Biol. 2011 Jul;34(3):416-20. Epub 2011 Jul 1. Polizzi A, Tesse R, Santostasi T, Diana A, Manca A, Logrillo VP, Cazzato MD, Pantaleo MG, Armenio L
Genotype-phenotype correlation in cystic fibrosis patients bearing [H939R;H949L] allele.
Genet Mol Biol. 2011 Jul;34(3):416-20. Epub 2011 Jul 1., [PMID:21931512]

Abstract [show]
Cystic fibrosis (CF) is caused by CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations. We ascertained five patients with a novel complex CFTR allele, with two mutations, H939R and H949L, inherited in cis in the same exon of CFTR gene, and one different mutation per patient inherited in trans in a wide population of 289 Caucasian CF subjects from South Italy. The genotype-phenotype relationship in patients bearing this complex allele was investigated. The two associated mutations were related to classical severe CF phenotypes.

Comments [show]

None has been submitted yet.

Sentences [show]
No. Sentence Comment
3 We ascertained five patients with a novel complex CFTR allele, with two mutations, H939R and H949L, inherited in cis in the same exon of CFTR gene, and one different mutation per patient inherited in trans in a wide population of 289 Caucasian CF subjects from South Italy. Login to comment
17 In 2005, we have described for the first time in the CF mutation database, the missense mutation H949L, a nucleotide change of A to T at base pair 2978 in exon 15 of CFTR gene, resulting in a substitution of histidine residue to leucine at codon 949, as potentially disease-associated allele variation. Login to comment
25 The Cystic Fibrosis Mutation Database lists the H939R missense mutation, a nucleotide substitution of A to G at base pair 2948 in the same exon of the mutation H949L, corresponding to a histidine to arginine amino acid change at codon 939. Login to comment
43 During the genetic characterization of the 289 enrolled CF patients a new complex allele [H939R;H949L] (Human Genome Variation Society nomenclature c:[2816A>G;2846A>T] http://www.hgvs.org/ mutnomen) was found in five unrelated patients, in whom the two CF-associated mutations, H939R and H949L, were both carried in the exon 15 on the same allele, as showed in Figure 1. Login to comment
46 We did not find patients bearing the H939R or the H949L mutations alone. Login to comment
48 Continuous arrows show the H939R mutation while the dashed arrows show the H949L mutation. Login to comment
70 We speculate that both mutations H939R and H949L might affect the second NBD of CFTR and have a role in altering the conductance of the chloride channel, but to our knowledge there are no reports on their functions. Login to comment
77 The complex alleles and their role in disease pathogenesis still remain a challenge for both researchers and clinicians, thus more information on our newly discovered complex allele [H939R;H949L] or on the H939R and the H949L mutations alone would help to study the effect on the phenotype of these rare mutations. Login to comment